Irinol

Irinotecan hydrochloride trihydrate.

IRINOL (Irinotecan Concentrate For Solution For Infusion 40mg/2ml): Each ml of the solution contains 20 mg of Irinotecan Hydrochloride Trihydrate of the active principle.
IRINOL (Irinotecan Concentrate For Solution For Infusion 100mg/5ml): Each ml of the solution contains 20 mg of Irinotecan Hydrochloride Trihydrate of the active principle.

Cytostatic topoisomerase I inhibitor. ATC Code: L01XX19.
Pharmacology: Pharmacodynamics: Irinotecan is a semi-synthetic derivative of camptothecin. It is an antineoplastic agent which acts as a specific inhibitor of DNA topoisomerase I. It is metabolised by carboxylesterase in most tissues to SN-38, which was found to be more active than irinotecan in purified topoisomerase I and more cytotoxic than irinotecan against several murine and human tumour cell lines. The inhibition of DNA topoisomerase I by irinotecan or SN-38 induces single-strand DNA lesions which blocks the DNA replication fork and are responsible for the cytotoxicity. This cytotoxic activity was found time-dependent and was specific to the S phase.
In vitro, irinotecan and SN-38 were not found to be significantly recognised by the P-glycoprotein MDR, and displays cytotoxic activities against doxorubicin and vinblastine resistant cell lines.
Furthermore, irinotecan has a broad antitumor activity in vivo against murine tumour models (P03 pancreatic ductal adenocarcinoma, MA16/C mammary adenocarcinoma, C38 and C51 colon adenocarcinomas) and against human xenografts (Co-4 colon adenocarcinoma, Mx-1 mammary adenocarcinoma, ST-15 and SC-16 gastric adenocarcinomas). Irinotecan is also active against tumors expressing the P-glycoprotein MDR (vincristine- and doxorubicin-resistant P388 leukaemia's).
Beside the antitumor activity of irinotecan, the most relevant pharmacological effect of irinotecan is the inhibition of acetylcholinesterase.
In combination therapy for the first-line treatment of metastatic colorectal carcinoma: In combination therapy with Folinic Acid and 5-Fluorouracil: In the every 2 weeks schedule, on day 1, the administration of IRINOL at 180 mg/m² once every 2 weeks is followed by infusion with folinic acid (200 mg/m² over a 2-hour intravenous infusion) and 5-fluorouracil (400 mg/m² as an intravenous bolus, followed by 600 mg/m² over a 22-hour intravenous infusion).
On day 2, folinic acid and 5-fluorouracil are administered at the same doses and schedules. In the weekly schedule, the administration of IRINOL at 80 mg/m² is followed by infusion with folinic acid (500 mg/m² over a 2-hour intravenous infusion) and then by 5-fluorouracil (2300 mg/m² over a 24-hour intravenous infusion) over 6 weeks.
In the weekly schedule, the incidence of severe diarrhoea in patients treated by IRINOL in combination with 5FU/FA and in patients treated by 5FU/FA alone. The incidence of severe neutropenia (neutrophil count < 500 cells/mm³) was in patients treated by IRINOL in combination with 5FU/FA and in patients treated by 5FU/FA alone.
In combination therapy with bevazicumab: Bevacizumab used in combination with IRINOL/5FU/FA as first-line treatment for metastatic carcinoma of the colon or rectum. The addition of bevacizumab to the combination of IRINOL/5FU/FA resulted in a statistically significant increase in overall survival. The clinical benefit, as measured by overall survival, was seen in all patient subgroups, including those defined by age, sex, and performance status, location of primary tumour, number of organs involved, and duration of metastatic disease.
In combination therapy with capecitabine: The support the use of capecitabine at a starting dose of 1000 mg/m² for 2 weeks every 3 weeks in combination with irinotecan for the first-line treatment of patients with metastatic colorectal cancer.
Sequential treatment consisted of first-line treatment with capecitabine (1250 mg/m² twice daily for 14 days), second-line irinotecan (350 mg/m² on day 1), and third-line combination of capecitabine (1000 mg/m² twice daily for 14 days) with oxaliplatin (130 mg/m² on day 1).
Combination treatment consisted of first-line treatment of capecitabine (1000 mg/m² twice daily for 14 days) combined with irinotecan (250 mg /m² on day 1) and second-line capecitabine (1000 mg/m² twice daily for 14 days) plus oxaliplatin (130 mg/m² on day 1). All treatment cycles were administered at intervals of 3 weeks. In first-line treatment the median progression-free survival in the intent-to-treat population was 5.8 months for capecitabine monotherapy and 7.8 months for irinotecan.
The intensity of the major toxicities encountered with IRINOL (e.g., leukoneutropenia and diarrhoea) are related to the exposure (AUC) to parent drug and metabolite SN-38. Significant correlations were observed between haematological toxicity (decrease in white blood cells and neutrophils at nadir) or diarrhoea intensity and both irinotecan and metabolite SN-38 AUC values in monotherapy.
Patients with Reduced UGT1A1 Activity: Uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) is involved in the metabolic deactivation of SN-38, the active metabolite of irinotecan to inactive SN-38 glucuronide (SN-38G). The UGT1A1 gene is highly polymorphic, resulting in variable metabolic capacities among individuals. One specific variation of the UGT1A1 gene includes a polymorphism in the promoter region known as the UGT1A1*28 variant. This variant and other congenital deficiencies in UGT1A1 expression (such as Crigler-Najjar and Gilbert's syndrome) are associated with reduced activity of this enzyme. Data from a meta-analysis indicate that individuals with Crigler-Najjar syndrome (types 1 and 2) or those who are homozygous for the UGT1A1*28 allele (Gilbert's syndrome) are at increased risk of haematological toxicity (grades 3 and 4) following administration of irinotecan at moderate or high doses (>150 mg/m²). A relationship between UGT1A1 genotype and the occurrence of irinotecan induced diarrhea was not established.
Patients known to be homozygous for UGT1A1*28 should be administered the normally indicated irinotecan starting dose. However, these patients should be monitored for haematologic toxicities. A reduced irinotecan starting dose should be considered for patients who have experienced prior haematologic toxicity with previous treatment. The exact reduction in starting dose in this patient population has not been established and any subsequent dose modifications should be based on a patient's tolerance of the treatment. There is at present insufficient data to conclude on clinical utility of UGT1A1 genotyping.
Pharmacokinetics: Absorption: At the end of the infusion, at the recommended dose of 350 mg/m², the mean peak plasma concentrations of irinotecan and SN-38 were 7.7 μg/ml and 56 ng/ml, respectively, and the mean area under the curve (AUC) values were 34 μg.h/ml and 451 ng.h/ml, respectively. A large interindividual variability in pharmacokinetic parameters is generally observed for SN-38.
Distribution: In vitro, plasma protein binding for irinotecan and SN-38 was approximately 65% and 95% respectively.
Biotransformation: Mass balance and metabolism studies with 14 C-labelled drug have shown that more than 50% of an intravenously administered dose of irinotecan is excreted as unchanged drug, with 33% in the faeces mainly via the bile and 22% in urine.
Two metabolic pathways account each for at least 12% of the dose: Hydrolysis by carboxylesterase into active metabolite SN-38, SN-38 is mainly eliminated by glucuronidation, and further by biliary and renal excretion (less than 0.5% of the irinotecan dose). The SN-38 glucuronite is subsequently probably hydrolysed in the intestine.
Cytochrome P450 3A enzymes-dependent oxidations resulting in opening of the outer piperidine ring with formation of APC (aminopentanoic acid derivate) and NPC (primary amine derivate).
Unchanged irinotecan is the major entity in plasma, followed by APC, SN-38 glucuronide and SN-38. Only SN-38 has significant cytotoxic activity.
Elimination: Irinotecan showed a biphasic or thriphasic elimination profile. The mean plasma clearance was 15 L/h/m² and the volume of distribution at steady state (Vss): 157 L/m². The mean plasma half-life of the first phase of the triphasic model was 12 minutes, of the second phase 2.5 hours, and the terminal phase half-life was 14.2 hours. SN-38 showed a biphasic elimination profile with a mean terminal elimination half-life of 13.8 hours.
Irinotecan clearance is decreased by about 40% in patients with bilirubinemia between 1.5 and 3 times the upper normal limit. In these patients a 200 mg/m² irinotecan dose leads to plasma drug exposure comparable to that observed at 350 mg/m² in cancer patients with normal liver parameters.
Linearity/non-linearity: A population pharmacokinetic analysis of irinotecan has been performed in patients with metastatic colorectal cancer, treated with various schedules and at different doses. All studies have shown that irinotecan (CPT-11) and SN-38 exposure increase proportionally with CPT-11 administered dose; their pharmacokinetics are independent of the number of previous cycles and of the administration schedule.

IRINOL (Irinotecan Concentrate For Solution For Infusion 20mg/ml) is indicated for the treatment of patients with advanced colorectal cancer: In combination with 5‑fluorouracil and folinic acid in patients without prior chemotherapy for advanced disease.
As a single agent in patients who have failed an established 5-fluorouracil containing treatment regimen.

Strictly follow the recommended dosage unless directed otherwise by the physician. All doses of irinotecan should be administered as an intravenous infusion over 30 to 90 minutes.
Single-agent dosage schedules: Single-agent dosage schedules have been extensively studied for metastatic colorectal cancer.
Starting dose: Weekly Dosage Schedule: The recommended single-agent starting dose of irinotecan is 125 mg/m². A lower starting dose may be considered (e.g., 100 mg/m²) for patients with any of the following conditions: prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6-week cycles, comprising weekly treatment for 4 weeks, followed by a 2-week rest.
Once-Every-2-Week Dosage Schedule: The usual recommended starting dose of irinotecan is 250 mg/m² every 2 weeks by intravenous infusion. A lower starting dose may be considered (e.g., 200 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Once-Every-3-Week Dosage Schedule: The usual recommended starting dose of irinotecan for the once-every-3-week dosage schedule is 350 mg/m². A lower starting dose may be considered (e.g., 300 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer.
Special populations: Elderly: The dose should be chosen carefully in this population due to their greater frequency of decreased biological functions. This population should require more intensive surveillance (See Pharmacology: Pharmacokinetics under Actions).
Patients with impaired hepatic function: In patients with hepatic dysfunction, the following starting doses are recommended: (See Tables 1 and 2.)

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Patients with impaired renal function: Studies in this population have not been conducted (See Pharmacology: Pharmacokinetics under Actions). Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.
Combination-agent dosage schedules: Starting Dose: Irinotecan in Combination with 5-Fluorouracil (5-FU) and folinic acid (FA): Irinotecan in combination with 5-FU and folinic acid is recommended for use in patients with metastatic colorectal cancer. For all regimens, the dose of folinic acid should be administered immediately after irinotecan, with the administration of 5-FU to occur immediately after receipt of folinic acid. The currently recommended regimens are shown as follows.
Regimen 1 (6-week cycle with bolus 5-FU/FA): The recommended starting dose is 125 mg/m² of irinotecan, 500 mg/m² bolus 5-FU, and 20 mg/m² bolus folinic acid.
Regimen 2 (6-week cycle with infusional 5-FU/FA): The recommended starting dose is 180 mg/m² of irinotecan, 400 mg/m² bolus 5-FU, 600 mg/m² 5-FU infusion, and 200 mg/m² folinic acid.
Lower starting doses may be considered for irinotecan (e.g., 100 mg/m²) and 5-FU (e.g., 400 mg/m²) for patients with any of the following conditions: age 65 years and older, prior extensive radiotherapy, performance status of 2, increased bilirubin levels, or gastric cancer. Treatment should be given in repeated 6-week cycles, comprising weekly treatment for 4 weeks, followed by a 2-week rest.
Duration of treatment: For both single-agent and combination-agent regimens, treatment with additional cycles of irinotecan may be continued indefinitely in patients who attain a tumor response or in patients whose cancer remains stable. Patients should be carefully monitored for toxicity and should be removed from therapy if unacceptable toxicity occurs that is not responsive to dose modification and routine supportive care.
Dose modification recommendations: The recommended dose modifications during a cycle of therapy and at the start of each subsequent cycle of therapy for single-agent dosage schedules are described in Table 3. These recommendations are based on toxicities commonly observed with the administration of irinotecan. For modifications at the start of a subsequent cycle of therapy, the dose of irinotecan should be decreased relative to the initial dose of the previous cycle.
The recommended dose modifications during a cycle of therapy and at the start of each subsequent cycle of therapy for irinotecan, 5-FU, and folinic acid are described in Table 4.
All dose modifications should be based on the worst preceding toxicity. A new cycle of therapy should not begin until the toxicity has recovered to Grade 2 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing irinotecan.
Recommended Dose Modifications for Single-agent Schedules: A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan. (See Table 3.)

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Recommended Dose Modifications for Irinotecan/5-Fluorouracil/Folinic Acid Combination Schedules: Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 hours before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/mm³, and the platelet count has recovered to ≥100,000/mm³, and treatment-related diarrhea is fully resolved.
Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan. (See Table 4.)

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There have been reports of overdosage at doses up to approximately twice the recommended therapeutic dose, which may be fatal. The most significant adverse reactions reported were severe neutropenia and severe diarrhoea.
There is no known antidote for IRINOL. Maximum supportive care should be instituted to prevent dehydration due to diarrhoea and to treat any infectious complications.

Chronic inflammatory bowel disease and/or bowel obstruction (see Precautions).
Hypersensitivity to the active substance(s) or to any of the excipients.
Lactation (see Use in Pregnancy & Lactation).
Bilirubin > 3 times the upper limit of the normal range (see Precautions).
Severe bone marrow failure.
WHO performance status > 2.
Concomitant use with St John's Wort (see Interactions).
Live attenuated vaccines (see Interactions).
For additional contraindications of cetuximab or bevacizumab or capecitabine, refer to the product information for these medicinal products.

The use of IRINOL should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a physician qualified in the use of anticancer chemotherapy.

Given the nature and incidence of adverse events, IRINOL will only be prescribed in the following cases after the expected benefits have been weighted against the possible therapeutic risks: In patients presenting a risk factor, particularly those with a WHO performance status = 2; In the few rare instances where patients are deemed unlikely to observe recommendations regarding management of adverse events (need for immediate and prolonged antidiarrhoeal treatment combined with high fluid intake at onset of delayed diarrhoea). Strict hospital supervision is recommended for such patients.
When IRINOL is used in monotherapy, it is usually prescribed with the every-3-week-dosage schedule. However, the weekly-dosage schedule may be considered in patients who may need a closer follow-up or who are at particular risk of severe neutropenia.
Delayed diarrhoea: Patients should be made aware of the risk of delayed diarrhoea occurring more than 24 hours after the administration of IRINOL and at any time before the next cycle. In monotherapy, the median time of onset of the first liquid stool was on day 5 after the infusion of IRINOL Patients should quickly inform their physician of its occurrence and start appropriate therapy immediately.
Patients with an increased risk of diarrhoea are those who had a previous abdominal and or pelvic radiotherapy, those with baseline hyperleucocytosis, those with performance status ≥ 2 and women. If not properly treated, diarrhoea can be lifethreatening, especially if the patient is concomitantly neutropenic.
As soon as the first liquid stool occurs, the patient should start drinking large volumes of beverages containing electrolytes and an appropriate antidiarrhoeal therapy must be initiated immediately. This antidiarrhoeal treatment will be prescribed by the department where IRINOL has been administered. After discharge from the hospital, the patients should obtain the prescribed drugs so that they can treat the diarrhoea as soon as it occurs. In addition, they must inform their physician or the department administering IRINOL when and or if diarrhoea is occurring.
The currently recommended antidiarrhoeal treatment consists of high doses of loperamide (4 mg for the first intake and then 2 mg every 2 hours). This therapy should continue for 12 hours after the last liquid stool and should not be modified. In no instance should loperamide be administered for more than 48 consecutive hours at these doses, because of the risk of paralytic ileus, nor for less than 12 hours.
In addition to the antibiotic treatment, hospitalisation is recommended for management of the diarrhoea, in the following cases: Diarrhoea associated with fever, Severe diarrhoea (requiring intravenous hydration), Diarrhoea persisting beyond 48 hours following the initiation of high-dose loperamide therapy.
Loperamide should not be given prophylactically, even in patients who experienced delayed diarrhoea at previous cycles. In patients who experienced severe diarrhoea, a reduction in dose is recommended for subsequent cycles.
Haematology: The frequency of NCI CTC grade 3 and 4 neutropenia has been significantly higher in patients who received previous pelvic/abdominal irradiation than in those who had not received such irradiation. Patients with baseline serum total bilirubin levels of 1.0 mg/dL or more have also had a significantly greater likelihood of experiencing first-cycle grade 3 or 4 neutropenia than those with bilirubin levels that were less than 1.0 mg/dL.
Weekly monitoring of complete blood cell counts is recommended during IRINOL treatment. Patients should be aware of the risk of neutropenia and the significance of fever. Febrile neutropenia (temperature > 38°C and neutrophil count ≤ 1,000 cells/mm³) should be urgently treated in the hospital with broad-spectrum intravenous antibiotics.
In patients who experienced severe haematological events, a dose reduction is recommended for subsequent administration.
There is an increased risk of infections and haematological toxicity in patients with severe diarrhoea. In patients with severe diarrhoea, complete blood cell counts should be performed.
Nausea and vomiting: A prophylactic treatment with antiemetics is recommended before each treatment with IRINOL. Nausea and vomiting have been frequently reported. Patients with vomiting associated with delayed diarrhoea should be hospitalised as soon as possible for treatment.
Acute cholinergic syndrome: If acute cholinergic syndrome appears (defined as early diarrhoea and various other signs and symptoms such as sweating, abdominal cramping, myosis and salivation), atropine sulphate (0.25 mg subcutaneously) should be administered unless clinically contraindicated.
These symptoms may be observed during or shortly after infusion of irinotecan, are thought to be related to the anticholinesterase activity of the irinotecan parent compound, and are expected to occur more frequently with higher irinotecan doses.
Caution should be exercised in patients with asthma. In patients who experienced an acute and severe cholinergic syndrome, the use of prophylactic atropine sulphate is recommended with subsequent doses of IRINOL.
Respiratory disorders: Interstitial pulmonary disease presenting as pulmonary infiltrates is uncommon during irinotecan therapy. Interstitial pulmonary disease can be fatal. Risk factors possibly associated with the development of interstitial pulmonary disease include the use of pneumotoxic drugs, radiation therapy and colony stimulating factors. Patients with risk factors should be closely monitored for respiratory symptoms before and during irinotecan therapy.
Extravasation: While irinotecan is not a known vesicant, care should be taken to avoid extravasation and the infusion site should be monitored for signs of inflammation. Should extravasation occur, flushing the site and application of ice is recommended.
Chronic inflammatory bowel disease and/or bowel obstruction: Patients must not be treated with IRINOL until resolution of the bowel obstruction.
Renal function: Increases in serum creatinine or blood urea nitrogen have been observed. There have been cases of acute renal failure.
These events have generally been attributed to complications of infection or to dehydration related to nausea, vomiting, or diarrhoea. Rare instances of renal dysfunction due to tumour lysis syndrome have also been reported.
Irradiation therapy: Patients who have previously received pelvic/abdominal irradiation are at increased risk of myelosuppression following the administration of irinotecan. Physicians should use caution in treating patients with extensive prior irradiation (e.g. >25% of bone marrow irradiated and within 6 weeks prior to start of treatment with irinotecan). Dosing adjustment may apply to this population.
Cardiac disorders: Myocardial ischaemic events have been observed following irinotecan therapy predominately in patients with underlying cardiac disease, other known risk factors for cardiac disease, or previous cytotoxic chemotherapy.
Consequently, patients with known risk factors should be closely monitored, and action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).
Vascular disorders: Irinotecan has been rarely associated with thromboembolic events (pulmonary embolism, venous thrombosis, and arterial thromboembolism) in patients presenting with multiple risk factors in addition to the underlying neoplasm.
Immunosuppressant effects/increased susceptibility to infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including irinotecan, may result in serious or fatal infections.
Vaccination with a live vaccine should be avoided in patients receiving irinotecan. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Others: Infrequent cases of renal insufficiency, hypotension or circulatory failure have been observed in patients who experienced episodes of dehydration associated with diarrhoea and/or vomiting, or sepsis.
Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.
Concomitant administration of irinotecan with a strong inhibitor (e.g. ketoconazole) or inducer (e.g. rifampicin, carbamazepine, phenobarbital, phenytoin, St John's Wort) of CYP3A4 may alter the metabolism of irinotecan and should be avoided.
Since this medicinal contains sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.
Effects On Ability To Drive And Use Machine: Patients should be warned about the potential for dizziness or visual disturbances which may occur within 24 hours following the administration of IRINOL, and advised not to drive or operate machinery if these symptoms occur.
Liver impairment: Liver function tests should be performed at baseline and before each cycle.
Weekly monitoring of complete blood counts should be conducted in patients with bilirubin ranging from 1.5 to 3 times ULN, due to decrease of the clearance of irinotecan and thus increasing the risk of hematotoxicity in this population.
Use in the Elderly: Due to the greater frequency of decreased biological functions, in particular hepatic function, in elderly patients, dose selection with IRINOL should be cautious in this population.

Women of child-bearing potential/Contraception in males and females: Women of childbearing potential and men have to use effective contraception during and up to 1 month and 3 months after treatment respectively.
Pregnancy: There is no data from the use of irinotecan in pregnant women. IRINOL should not be used during pregnancy unless clearly necessary.
Breast-feeding: It is not known whether irinotecan is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast-feeding should be discontinued for the duration of IRINOL therapy.
Fertility: There are no human data on the effect of irinotecan on fertility.

The most common, dose-limiting adverse reactions of irinotecan are delayed diarrhoea (occurring more than 24 hours after administration) and blood disorders including neutropenia, anaemia and thrombocytopenia.
Neutropenia is a dose-limiting toxic effect. Neutropenia was reversible and not cumulative; the median day to nadir was 8 days whatever the use in monotherapy or in combination therapy.
Very commonly severe transient acute cholinergic syndrome was observed.
The main symptoms were defined as early diarrhoea and various other symptoms such as abdominal pain, sweating, myosis and increased salivation occurring during or within the first 24 hours after the infusion of IRINOL. These symptoms disappear after atropine administration.
MONOTHERAPY: (See Table 5.)

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Laboratory tests: Transient and mild to moderate increases in serum levels of either transaminases, alkaline phosphatase or bilirubin were observed in the patients, respectively, in the absence of progressive liver metastasis.
Transient and mild to moderate increases of serum levels of creatinine have been observed in the patients.
COMBINATION THERAPY: Adverse reactions detailed in this section refer to irinotecan.
There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa. In combination with cetuximab, additional reported adverse reactions were those expected with cetuximab, such as acneform rash. For information on adverse reactions on irinotecan in combination with cetuximab, also refer to their respective summary of product characteristics.
Adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Very common, all grade adverse drug reactions: thrombosis/embolism; Common, all grade adverse drug reactions: hypersensitivity reaction, cardiac ischemia/infarction; Common, grade 3 and grade 4 adverse drug reactions: febrile neutropenia. For complete information on adverse reactions of capecitabine, refer to the capecitabine summary product of characteristics.
Grade 3 and Grade 4 adverse drug reactions reported in patients treated with capecitabine in combination with irinotecan and bevacizumab in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy include: Common, grade 3 and grade 4 adverse drug reactions: neutropenia, thrombosis/embolism, hypertension, and cardiac ischemia/infarction. For complete information on adverse reactions of capecitabine and bevacizumab, refer to the respective capecitabine and bevacizumab summary of product characteristics.
Grade 3 hypertension was the principal significant risk involved with the addition of bevacizumab to bolus IRINOL/5-FU/FA. In addition, there was a small increase in the grade 3/4 chemotherapy adverse events of diarrhoea and leukopenia with this regimen compared to patients receiving bolus IRINOL/5-FU/FA alone. For other information on adverse reactions in combination with bevacizumab, refer to the bevacizumab summary of product characteristics.
Safety data of adverse reactions from clinical studies demonstrate very commonly observed NCI Grade 3 or 4 possibly or probably-related adverse events in the blood and the lymphatic system disorders, gastrointestinal disorders, and skin and subcutaneous tissue disorders MedDRA System Organ Classes.
The following adverse reactions considered to be possibly or probably related to the administration of IRINOL have been reported from 145 patients treated by IRINOL in combination therapy with 5FU/FA in every 2 weeks schedule at the recommended dose of 180 mg/m². (See Table 6.)

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Laboratory tests: Transient serum levels (grades 1 and 2) of either SGPT, SGOT, alkaline phosphatase or bilirubin were observed in the patients, respectively, in the absence of progressive liver metastasis. Transient grade 3 were observed in the patients, respectively. No grade 4 was observed.
Increases of amylase and/or lipase have been very rarely reported. Rare cases of hypokalaemia and hyponatremia mostly related with diarrhoea and vomiting have been reported.
POST-MARKETING SURVEILLANCE: Side effects have been summarised in the table as follows with MedDRA frequencies. (See Table 7.)

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Concomitant use contraindicated (see Contraindications): Yellow fever vaccine: Risk of fatal generalised reaction to vaccines.
Saint John's Wort: Decrease in the active metabolite of irinotecan, SN-38, plasma levels Irinotecan 350 mg/m² was co-administered with St. John's Wort (Hypericum perforatum) 900 mg, a 42% decrease in the active metabolite of irinotecan, SN-38, plasma concentrations was observed. As a result, St. John's Wort should not be administered with irinotecan.
Live attenuated vaccines: Risk of generalised reaction to vaccines, possibly fatal. Concomitant use is contraindicated during treatment with irinotecan and for 6 months following discontinuation of chemotherapy. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Concomitant use not recommended (see Precautions): Concurrent administration of irinotecan with a strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) may alter the metabolism of irinotecan and should be avoided (see Precautions).
Strong CYP3A4 and/or UGT1A1 inducing medicinal products (e.g. rifampicin, carbamazepine, phenobarbital or phenytoin): Risk of reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. Concomitant administration of CYP3A4-inducing anticonvulsant medicinal products leads to reduced exposure to irinotecan, SN-38 and SN-38 glucuronide and reduced pharmacodynamic effects. The effects of such anticonvulsant medicinal products were reflected by a decrease in AUC of SN-38 and SN-38G by 50% or more. In addition to induction of CYP3A4 enzymes, enhanced glucuronidation and enhanced biliary excretion may play a role in reducing exposure to irinotecan and its metabolites. Additionally with phenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic medicinal products.
Strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, voriconazole, posaconazole, protease inhibitors, clarithromycine, erythromycine, telithromycine): A study has shown that the co-administration of ketoconazole resulted in a decrease in the AUC of APC of 87% and in an increase in the AUC of SN-38 of 109% in comparison to irinotecan given alone.
UGT1A1 inhibitors (e.g. atazanavir, ketoconazole, regorafenib): Risk to increase systemic exposure to SN-38, the active metabolite of irinotecan. Physicians should take this into consideration if the combination is unavoidable.
Other CYP3A4 inhibitors (e.g. crizotinib, idelalisib): Risk of increase in irinotecan toxicity, due to a decrease in irinotecan metabolism by crizotinib or idelalisib.
Caution for use: Vitamin K antagonists: Increased risk of haemorrhage and thrombotic events in tumoral diseases. If vitamin K antagonists are indicated, an increased frequency in the monitoring of INR (International Normalised Ratio) is required.
Concomitant use to take into consideration: Immunodepressant agents (e.g. ciclosporine, tacrolimus): Excessive immunosuppression with risk of lymphoproliferation.
Neuromuscular blocking agents: Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Since IRINOL has anticholinesterase activity, medicinal products with anticholinesterase activity may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarising medicinal products may be antagonised.
Other combinations: 5-fluorouracil/folinic acid: Coadministration of 5-fluorouracil/folinic acid in the combination regimen does not change the pharmacokinetics of irinotecan.
Bevacizumab: No significant effect of bevacizumab on the pharmacokinetics of irinotecan and its active metabolite SN-38. However, this does not preclude any increase of toxicities due to their pharmacological properties.
Cetuximab: There is no evidence that the safety profile of irinotecan is influenced by cetuximab or vice versa.

Instructions for Use: As with other antineoplastic agents, IRINOL must be prepared and handled with caution. The use of glasses, mask and gloves is required.
If IRINOL solution or infusion solution should come into contact with the skin, wash immediately and thoroughly with soap and water. If IRINOL solution or infusion solution should come into contact with the mucous membranes, wash immediately with water.
Preparation for the intravenous infusion administration: As with any other injectable medicinal products, the IRINOL solution must be prepared aseptically.
If any precipitate is observed in the vials or after dilution, the product should be discarded according to standard procedures for cytotoxic agents.
Aseptically withdraw the required amount of IRINOL solution from the vial with a calibrated syringe and inject into a 250 ml infusion bag or bottle containing either 0.9% sodium chloride solution or 5% glucose solution. The infusion should then be thoroughly mixed by manual rotation.
The final concentration of Irinol (Irinotecan Concentrate for Solution for Infusion 20mg/ml) after dilution according to the above information is between 0.12 mg/ml to 3.0 mg/ml.
Incompatibilities: None known.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Unopened vial: Store below 30°C and store the vial in the original packaging to protect from light.
After further dilution: The solution is physically and chemically stable with infusion solutions; 0.9% Sodium Chloride Injection and 5% Dextrose Injection for up to 24 hours at room temperature (below 30°C) and up to 48 hours when stored at 2°C-8°C.
It is recommended that to reduce the microbiological hazard, the infusion solutions should be prepared immediately before use and infusion commenced as soon as practicable after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2°C to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Shelf-Life: Unopened vial: The shelf-life of unopened vials is 24 months.

Cytotoxic Chemotherapy

L01CE02 - irinotecan ; Belongs to the class of Topoisomerase 1 (TOP1) inhibitors. Used in the treatment of cancer.

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